The aging brain: sleep, the circadian clock and exercise.

Aging is a multifactorial process likely stemming from damage accumulation and/or a decline in maintenance and repair mechanisms in the organisms that eventually determine their lifespan. In our review, we focus on the morphological and functional alterations that the aging brain undergoes affecting sleep and the circadian clock in both human and rodent models. Although both species share mammalian features, differences have been identified on several experimental levels, which we outline in this review. Additionally, we delineate some challenges on the preferred analysis and we suggest that a uniform route is followed so that findings can be smoothly compared. We conclude by discussing potential interventions and highlight the influence of physical exercise as a beneficial lifestyle intervention, and its effect on healthy aging and longevity. We emphasize that even moderate age-matched exercise is able to ameliorate several aging characteristics as far as sleep and circadian rhythms are concerned, independent of the species studied.

Chloride cotransporter KCC2 is essential for GABAergic inhibition in the SCN.

One of the principal neurotransmitters of the central nervous system is GABA. In the adult brain, GABA is predominantly inhibitory, but there is growing evidence indicating that GABA can shift to excitatory action depending on environmental conditions. In the mammalian central circadian clock of the suprachiasmatic nucleus (SCN) GABAergic activity shifts from inhibition to excitation when animals are exposed to long day photoperiod. The polarity of the GABAergic response (inhibitory versus excitatory) depends on the GABA equilibrium potential determined by the intracellular Cl- concentration ([Cl-]i). Chloride homeostasis can be regulated by Cl- cotransporters like NKCC1 and KCC2 in the membrane, but the mechanisms for maintaining [Cl-]i are still under debate. This study investigates the role of KCC2 on GABA-induced Ca2+ transients in SCN neurons from mice exposed to different photoperiods. We show for the first time that blocking KCC2 with the newly developed blocker ML077 can cause a shift in the polarity of the GABAergic response. This will increase the amount of excitatory responses in SCN neurons and thus cause a shift in excitatory/inhibitory ratio. These results indicate that KCC2 is an essential component in regulating [Cl-]i and the equilibrium potential of Cl- and thereby determining the sign of the GABAergic response. Moreover, our data suggest a role for the Cl- cotransporters in the switch from inhibition to excitation observed under long day photoperiod.

Decrease in scale invariance of activity fluctuations with aging and in patients with suprasellar tumors.

Motor activity in healthy young humans displays intrinsic fluctuations that are scale-invariant over a wide range of time scales (from minutes to hours). Human postmortem and animal lesion studies showed that the intact function of the suprachiasmatic nucleus (SCN) is required to maintain such scale-invariant patterns. We therefore hypothesized that scale invariance is degraded in patients treated for suprasellar tumors that compress the SCN. To test the hypothesis, we investigated 68 patients with nonfunctioning pituitary macroadenoma and 22 patients with craniopharyngioma, as well as 72 age-matched healthy controls (age range 21.0-70.6 years). Spontaneous wrist locomotor activity was measured for 7 days with actigraphy, and detrended fluctuation analysis was applied to assess correlations over a range of time scales from minutes to 24 h. For all the subjects, complex scale-invariant correlations were only present for time scales smaller than 1.5 h, and became more random at time scales 1.5-10 h. Patients with suprasellar tumors showed a larger decrease in correlations at 1.5-10 h as compared to healthy controls. Within healthy subject, gender and age >33 year were associated with attenuated scale invariance. Conversely, activity patterns at time scales between 10 and 24 h were significantly more regular than all other time scales, and this was mostly associated with age. In conclusion, scale invariance is degraded in healthy subjects at the ages of >33 year as characterized by attenuation of correlations at time scales 1.5-10 h. In addition, scale invariance was more degraded in patients with suprasellar tumors as compared to healthy subjects.

Levofloxacin-Induced QTc Prolongation Depends on the Time of Drug Administration.

Understanding the factors influencing a drug's potential to prolong the QTc interval on an electrocardiogram is essential for the correct evaluation of its safety profile. To explore the effect of dosing time on drug-induced QTc prolongation, a randomized, crossover, clinical trial was conducted in which 12 healthy male subjects received levofloxacin at 02:00, 06:00, 10:00, 14:00, 18:00, and 22:00. Using a pharmacokinetic-pharmacodynamic (PK-PD) modeling approach to account for variations in PKs, heart rate, and daily variation in baseline QT, we find that the concentration-QT relationship shows a 24-hour sinusoidal rhythm. Simulations show that the extent of levofloxacin-induced QT prolongation depends on dosing time, with the largest effect at 14:00 (1.73 (95% prediction interval: 1.56-1.90) ms per mg/L) and the smallest effect at 06:00 (-0.04 (-0.19 to 0.12) ms per mg/L). These results suggest that a 24-hour variation in the concentration-QT relationship could be a potentially confounding factor in the assessment of drug-induced QTc prolongation.

Neural activity in the suprachiasmatic circadian clock of nocturnal mice anticipating a daytime meal.

Circadian rhythms in mammals are regulated by a system of circadian oscillators that includes a light-entrainable pacemaker in the suprachiasmatic nucleus (SCN) and food-entrainable oscillators (FEOs) elsewhere in the brain and body. In nocturnal rodents, the SCN promotes sleep in the day and wake at night, while FEOs promote an active state in anticipation of a predictable daily meal. For nocturnal animals to anticipate a daytime meal, wake-promoting signals from FEOs must compete with sleep-promoting signals from the SCN pacemaker. One hypothesis is that FEOs impose a daily rhythm of inhibition on SCN output that is timed to permit the expression of activity prior to a daytime meal. This hypothesis predicts that SCN activity should decrease prior to the onset of anticipatory activity and remain suppressed through the scheduled mealtime. To assess the hypothesis, neural activity in the SCN of mice anticipating a 4-5-h daily meal in the light period was measured using FOS immunohistochemistry and in vivo multiple unit electrophysiology. SCN FOS, quantified by optical density, was significantly reduced at the expected mealtime in food-anticipating mice with access to a running disk, compared to ad libitum-fed and acutely fasted controls. Group differences were not significant when FOS was quantified by other methods, or in mice without running disks. SCN electrical activity was markedly decreased during locomotion in some mice but increased in others. Changes in either direction were concurrent with locomotion, were not specific to food anticipation, and were not sustained during longer pauses. Reduced FOS indicates a net suppression of SCN activity that may depend on the intensity or duration of locomotion. The timing of changes in SCN activity relative to locomotion suggests that any effect of FEOs on SCN output is mediated indirectly, by feedback from neural or systemic correlates of locomotion.

Population Pharmacokinetic Model Characterizing 24-Hour Variation in the Pharmacokinetics of Oral and Intravenous Midazolam in Healthy Volunteers.

Daily rhythms in physiology may affect the pharmacokinetics of a drug. The aim of this study was to evaluate 24-hour variation in the pharmacokinetics of the CYP3A substrate midazolam. Oral (2 mg) and intravenous (1 mg) midazolam was administered at six timepoints throughout the 24-hour period in 12 healthy volunteers. Oral bioavailability (population mean value [RSE%] of 0.28 (7.1%)) showed 24-hour variation that was best parameterized as a cosine function with an amplitude of 0.04 (17.3%) and a peak at 12:14 in the afternoon. The absorption rate constant was 1.41 (4.7%) times increased after drug administration at 14:00. Clearance (0.38 L/min (4.8%)) showed a minor 24-hour variation with an amplitude of 0.03 (14.8%) L/min and a peak at 18:50. Simulations show that dosing time minimally affects the concentration time profiles after intravenous administration, while concentrations are higher during the day compared to the night after oral dosing, reflecting considerable variation in intestinal processes.

Plasticity of circadian clocks and consequences for metabolism.

The increased prevalence of metabolic disorders and obesity in modern society, together with the widespread use of artificial light at night, have led researchers to investigate whether altered patterns of light exposure contribute to metabolic disorders. This article discusses the experimental evidence that perturbed environmental cycles induce rhythm disorders in the circadian system, thus leading to metabolic disorders. This notion is generally supported by animal studies. Distorted environmental cycles, including continuous exposure to light, affect the neuronal organization of the central circadian pacemaker in the suprachiasmatic nucleus (SCN), its waveform and amplitude of the rhythm in electrical activity. Moreover, repeated exposure to a shifted light cycle or the application of dim light at night are environmental cues that cause a change in SCN function. The effects on the SCN waveform are the result of changes in synchronization among the SCN's neuronal cell population, which lead consistently to metabolic disturbances. Furthermore, we discuss the effects of sleep deprivation and the time of feeding on metabolism, as these factors are associated with exposure to disturbed environmental cycles. Finally, we suggest that these experimental studies reveal a causal relationship between the rhythm disorders and the metabolic disorders observed in epidemiological studies performed in humans.

Cognitive functioning associated with stimulant use in patients with non-affective psychosis, their unaffected siblings and healthy controls.

BACKGROUND: Little is known about the effect of stimulant use (amphetamines, cocaine, ecstasy) on cognitive functioning in schizophrenia patients. The current study examined (1) whether recency and frequency of stimulant use is associated with cognitive functioning and (2) whether these associations differ between psychotic patients, their unaffected siblings and controls. METHOD: Participants completed a comprehensive cognitive test battery. Stimulant use was assessed by urinalysis and by the Composite International Diagnostic Interview (CIDI). Using random effects regression models, the main effects of Stimulant Use and the interaction with Diagnostic Status on cognitive functioning were assessed. RESULTS: The interaction term between Stimulant Use and Diagnostic Status was not significant for any of the cognitive outcome variables, indicating similar effects of stimulant use in all three groups. Recent stimulant users showed more errors deficit in verbal learning in comparison to never users (Cohen's d = -0.60, p < 0.005). Lifetime frequent stimulant use was significantly associated with worse immediate and delayed verbal recall, working memory and acquired knowledge (Cohen's d = -0.22 to -0.29, p < 0.005). Lifetime infrequent stimulant use was not associated with significant cognitive alterations in comparison to never use. CONCLUSIONS: The presence of cognitive deficits associated with lifetime stimulant use is dependent on the frequency of use, with no observed deficits in infrequent users and modest negative effects in frequent users.

A strategic development model for the role of the biomedical physicist in the education of healthcare professionals in Europe.

This is the third of a series of articles targeted at biomedical physicists providing educational services to other healthcare professions, whether in a university faculty of medicine/health sciences or otherwise (e.g., faculty of science, hospital-based medical physics department). The first paper identified the past and present role of the biomedical physicist in the education of the healthcare professions and highlighted issues of concern. The second paper reported the results of a comprehensive SWOT (strengths, weaknesses, opportunities, threats) audit of that role. In this paper we present a strategy for the development of the role based on the outcomes of the SWOT audit. The research methods adopted focus on the importance of strategic planning at all levels in the provision of educational services. The analytical process used in the study was a pragmatic blend of the various theoretical frameworks described in the literature on strategic planning research as adapted for use in academic role development. Important results included identification of the core competences of the biomedical physicist in this context; specification of benchmarking schemes based on experiences of other biomedical disciplines; formulation of detailed mission and vision statements; gap analysis for the role. The paper concludes with a set of strategies and specific actions for gap reduction.

Cannabis and cognitive performance in psychosis: a cross-sectional study in patients with non-affective psychotic illness and their unaffected siblings.

BACKGROUND: The relationship between cannabis use and cognitive functioning in patients with psychosis has yielded contradictory findings. In individuals at genetic high risk for psychosis, information is sparse. The aim of this study was to assess the association between recency and frequency of cannabis use and cognitive functioning in patients with psychosis and their unaffected siblings. METHOD: We conducted a cross-sectional study in 956 patients with non-affective psychosis, 953 unaffected siblings, and 554 control subjects. Participants completed a cognitive test battery including assessments of verbal learning, set shifting, sustained attention, processing speed, working memory, acquired knowledge, reasoning and problem solving and social cognition. Cannabis use was assessed by urinalysis and by the Composite International Diagnostic Interview. Using random-effect regression models the main effects of cannabis (recency and frequency) and the interaction with status (patient, sibling, control) on cognitive functioning were assessed. RESULTS: Current cannabis use was associated with poorer performance on immediate verbal learning, processing speed and working memory (Cohen's d -0.20 to -0.33, p<0.005). Lifetime cannabis use was associated with better performance on acquired knowledge, facial affect recognition and face identity recognition (Cohen's d+0.17 to +0.33, p<0.005). There was no significant interaction between cannabis and status on cognitive functioning. CONCLUSIONS: Lifetime cannabis-using individuals might constitute a subgroup with a higher cognitive potential. The residual effects of cannabis may impair short-term memory and processing speed.

A comprehensive SWOT audit of the role of the biomedical physicist in the education of healthcare professionals in Europe.

Although biomedical physicists provide educational services to the healthcare professions in the majority of universities in Europe, their precise role with respect to the education of the healthcare professions has not been studied systematically. To address this issue we are conducting a research project to produce a strategic development model for the role using the well-established SWOT (Strengths, Weaknesses, Opportunities, Threats) methodology. SWOT based strategic planning is a two-step process: one first carries out a SWOT position audit and then uses the identified SWOT themes to construct the strategic development model. This paper reports the results of a SWOT audit for the role of the biomedical physicist in the education of the healthcare professions in Europe. Internal Strengths and Weaknesses of the role were identified through a qualitative survey of biomedical physics departments and biomedical physics curricula delivered to healthcare professionals across Europe. External environmental Opportunities and Threats were identified through a systematic survey of the healthcare, healthcare professional education and higher education literature and categorized under standard PEST (Political, Economic, Social-Psychological, Technological-Scientific) categories. The paper includes an appendix of terminology. Defined terms are marked with an asterisk in the text.

The role of the biomedical physicist in the education of the healthcare professions: an EFOMP project.

The role of the biomedical physicist in the education of the healthcare professions has not yet been studied in a systematic manner. This article presents the first results of an EFOMP project aimed at researching and developing this important component of the role of the biomedical physicist. A background to the study expands on the reasons that led to the need for the project. This is followed by an extensive review of the published literature regarding the role. This focuses mainly on the teaching contributions within programmes for physicians, diagnostic radiographers, radiation therapists, and the postgraduate medical specializations of radiology, radiotherapy, interventional radiology and cardiology. Finally a summary list of the specific research objectives that need to be immediately addressed is presented. These are the carrying out of a Europe-wide position audit for the role, the construction of a strategic role development model and the design of a curriculum development model suitable for modern healthcare professional education.

[In time for Beijing: influence of the biological clock on athletic performance]. / Op tijd voor Beijing: invloed van de biologische klok op sportprestaties.

Circadian rhythms are a common characteristic ofmulticellular organisms and evolved as an adaptation to the earth's rotation on its axis. In humans, circadian rhythms are regulated by suprachiasmatic nuclei located at the base of the hypothalamus. The suprachiasmatic nuclei function as a biological clock that controls the daily rhythms of nearly all physiological functions. External light synchronises the endogenous clock to the environmental light-dark cycle. When travelling rapidly across multiple time zones, the endogenous clock must adjust to the new time. During the period of adjustment, many physiological circadian rhythms become desynchronised and jet lag occurs. Few studies have analysed the influence of jet lag on athletic performance. These studies indicate that performance levels can decline during jet lag. This seems to be a result of the desynchronized physiological state and sleep disturbances, leading to suboptimal values of blood pressure, heart rate, body temperature, and muscle strength. We give some advice for athletes who must cross multiple time zones shortly before a competition.

Phase differences between SCN neurons and their role in photoperiodic encoding; a simulation of ensemble patterns using recorded single unit electrical activity patterns.

In mammals, a major circadian pacemaker is located in the suprachiasmatic nuclei (SCN), at the base of the anterior hypothalamus. The pacemaker controls daily rhythms in behavioral, physiological and endocrine functions and is synchronized to the external light-dark cycle via the retinohypothalamic tract. The SCN are also involved in photoperiodic processes. Changes in day-length are perceived by the SCN, and result in a compression or decompression of the SCN ensemble pattern, which appears to be effectuated by changes in phase relationship among oscillating neurons. By simulation experiments, we have previously shown that the duration of the single unit activity pattern is of minor importance for the broadness of the population activity peak. Instead, the phase distribution among neurons is leading to substantial differences in the broadness of the population pattern. We now show that the combination of (i) changes in the single unit activity pattern and (ii) changes in the phase distribution among oscillating neurons is also effective to encode photoperiodic information. Moreover, we simulated the ensemble waveform of the SCN with recently recorded single unit electrical activity patterns of mice under long and short photoperiods. We show that these single unit activity patterns cannot account for changes in the population waveform of the SCN unless their phase distribution is changed. A narrow distribution encodes for short photoperiods, while a wider distribution is required to encode long photoperiods. The present studies show that recorded patterns in single unit activity rhythms, measured under long and short day conditions, can be used in simulation experiments and are informative in showing which attributes of the neuronal discharge patterns leads to the capacity of the SCN to encode photoperiod.

Convergence of circadian and sleep regulatory mechanisms on hypocretin-1.

Hypocretin is a potential regulator of sleep and wakefulness and its levels fluctuate with the day-night cycle with high levels during the animal's activity period. Whether the daily fluctuations are driven endogenously or by external light cycles is unknown. We investigated the circadian and homeostatic regulation of hypocretin in the absence of environmental light cycles. To this purpose we performed repetitive samplings of cerebrospinal fluid in rats through implanted microcannulas in the cisterna magna and determined hypocretin-1 levels by radioimmunoassay. These experiments were also performed in rats that received a lesion of the suprachiasmatic nucleus (SCN), a major pacemaker for circadian rhythms in mammals. The results showed sustained rhythmicity of hypocretin in constant dim red light in control animals. SCN-lesioned animals showed no circadian rhythms in hypocretin and mean hypocretin levels were remarkably low. The results indicate that the SCN is indispensable for rhythmicity in hypocretin and induces a daily increase in hypocretin levels during the animal's active phase. Additional sleep deprivation experiments were carried out to investigate homeostatic regulation of hypocretin. Hypocretin levels increased in response to sleep deprivation in both control and SCN-lesioned animals, demonstrating that sleep homeostatic control of hypocretin occurs independently from the SCN. Our data indicate that the circadian pacemaker of the SCN and sleep homeostatic mechanisms converge on one single sleep regulatory substance.

Comparing spot electrode arrangements for electric impedance cardiography.

This study investigates whether an arrangement with nine spot electrodes, for thoracic bio-impedance cardiography, can be replaced by an arrangement with five spot electrodes. The study was conducted on 15 healthy subjects, six females and nine males, in supine rest. The variables obtained from the measurements were the mean of the impedance of the thorax segment between the recording electrodes, the maximum negative deflection of the first derivative of the thoracic impedance, the left ventricular ejection time and an estimate of left ventricular stroke volume. An analysis of variance for a randomized complete block design was used to determine whether significant differences exist in the group means of the observed variables between six different electrode arrangements. If no statistically significant differences were found in these group means between pairs of arrangements, Bland and Altman analyses were used to determine the differences in the observed variables between pairs of arrangements for individual subjects. This study concludes that reducing the number of spot electrodes from nine to five, does not yield significant differences in the group means of the observed variables, but it could result in large differences in the values of these variables for individual subjects.

Phase differences in electrical discharge rhythms between neuronal populations of the left and right suprachiasmatic nuclei.

The circadian pacemaker of the suprachiasmatic nuclei is a complex multioscillator system, which controls circadian and seasonal rhythmicity. A number of clock genes have been identified that play a key role in the generation of circadian rhythms. These clock genes are expressed in a circadian manner as has been shown in mice, rats and hamsters. The time at which their expression reaches peak values differs among the several genes. Expression profiles for a specific gene may also differ among subdivisions of the suprachiasmatic nuclei. It has been shown that mPer1 peaks slightly out of phase in the left and right suprachiasmatic nuclei and that the rhythm in c-fos expression is significantly different between the dorsomedial and ventrolateral regions. In the special case that the animal shows splitting of its locomotor activity pattern, mPer1 in the left and right suprachiasmatic nuclei appeared to oscillate in antiphase. Whether the molecular organization within the suprachiasmatic nuclei plays a role in seasonal rhythmicity, allowing animals to track daylength and become reproductive at the proper phase of the annual cycle, receives increasing interest (). The differences in peak expression times that exist between different genes, and the spatial differences in peak time for single genes, are suggestive of a genetic mechanism underlying the multioscillator structure. It is unknown, however, whether phase differences that are observed at the molecular level exist at the level of electrical activity rhythms in the suprachiasmatic nuclei in order to become potentially functional. In this study we investigated the presence of phase differences in neuronal discharge rhythms in the suprachiasmatic nuclei of the rat. To this purpose we combined simultaneous electrophysiological recordings of neuronal populations in the left and right suprachiasmatic nuclei with a detailed analysis of the phase relationship between them. The results demonstrate that neuronal subpopulations of the suprachiasmatic nuclei show phase differences both in their peak and half-maximum times of up to 4 h. We propose that these phase differences may play a role in the plasticity of the circadian timing system.

Relationship between internal risk factors for development of decubitus ulcers and the blood flow response following pressure load.

The objective of this study was to investigate the extent to which internal risk factors for the development of decubitus ulcers are related to the blood flow response following the relief of a pressure load. There were 122 nursing home patients (43 men, 69 women, mean age: 81 +/- 8 years; range: 60-97). The following potential, internal risk factors for the development of decubitus ulcers were assessed: chronic disorders (diabetes mellitus, cardiovascular disease [congestive heart failure, history of myocardial infarct or angina pectoris] and cerebrovascular accident), fever, blood pressure, nutritional status, serum hemoglobin concentration, and serum urea and serum creatinine concentrations. Skin temperature response (latency time and total response time) was measured following relief of a 100 kPa test pressure. The presence of cardiovascular disease, cerebrovascular accident, poor nutritional condition, high serum urea and male gender showed a significant relationship with an impaired blood flow response. The delayed latency found showed a similarity to the so-called "no-reflow phenomenon." The association of cardiovascular disease and a cerebrovascular accident with a delay in the blood flow response may result from endothelial damage. A poor nutritional condition may be associated with a deficit of scavengers of oxygen-derived free radicals. The presence of free radicals may damage endothelium during reperfusion, thus influencing the blood flow response. The association of high serum urea with delayed vasodilatation may theoretically be explained by the association of serum urea and impaired kidney functioning, since the kidney is an important organ in the production of vasoactive substances. Serum urea can also be considered a measure for nutritional condition. Gender may function as a substitute for other, unmeasured factors that are related to blood flow response.

Opposing effects of behavioural activity and light on neurons of the suprachiasmatic nucleus.

The mammalian circadian pacemaker is located in the suprachiasmatic nuclei. It can be shifted in phase by photic cues and by the behavioural activity of the animal. When presented together, light and behavioural activity attenuate each others' phase-shifting effect. Still unclear is how behavioural activity affects the suprachiasmatic nuclei and how it interacts with photic information. Previously, we reported the occurrence of behaviourally induced suppressions of neuronal activity. The present study investigates the characteristics of these suppressions as a function of circadian time and, additionally, in the presence of photic cues. We performed long-term multiunit activity recordings of neurons in freely moving rats and found that these suppressions of neuronal firing in the suprachiasmatic nucleus occurred at every phase of the circadian cycle. The magnitude of the suppressions showed a circadian variation, with larger suppressions during subjective day. When a light pulse was applied during a suppression, light and activity appeared to oppose each others' effects within the recorded population of neurons. The resulting discharge level appeared to be the sum of both responses. The opposing effects of light and activity were also found in single unit recordings, indicating that photic and behavioural stimuli interact at the level of a single neuron.

Light-Induced resetting of the circadian pacemaker: quantitative analysis of transient versus steady-state phase shifts.

The suprachiasmatic nuclei of the hypothalamus contain the major circadian pacemaker in mammals, driving circadian rhythms in behavioral and physiological functions. This circadian pacemaker's responsiveness to light allows synchronization to the light-dark cycle. Phase shifting by light often involves several transient cycles in which the behavioral activity rhythm gradually shifts to its steady-state position. In this article, the authors investigate in Syrian hamsters whether a phase-advancing light pulse results in immediate shifts of the PRC at the next circadian cycle. In a first series of experiments, the authors aimed a light pulse at CT 19 to induce a phase advance. It appeared that the steady-state phase advances were highly correlated with activity onset in the first and second transient cycle. This enabled them to make a reliable estimate of the steady-state phase shift induced by a phase-advancing light pulse on the basis of activity onset in the first transient cycle. In the next series of experiments, they presented a light pulse at CT 19, which was followed by a second light pulse aimed at the delay zone of the PRC on the next circadian cycle. The immediate and steady-state phase delays induced by the second light pulse were compared with data from a third experiment in which animals received a phase-delaying light pulse only. The authors observed that the waveform of the phase-delay part of the PRC (CT 12-16) obtained in Experiment 2 was virtually identical to the phase-delay part of the PRC for a single light pulse (obtained in Experiment 3). This finding allowed for a quantitative assessment of the data. The analysis indicates that the delay part of the PRC-between CT 12 and CT 16-is rapidly reset following a light pulse at CT 19. These findings complement earlier findings in the hamster showing that after a light pulse at CT 19, the phase-advancing part of the PRC is immediately shifted. Together, the data indicate that the basis for phase advancing involves rapid resetting of both advance and delay components of the PRC.